Dual PI3K/AKT/mTOR and CDK4/6 inhibition suppresses survivin to overcome uterine dedifferentiated endometrial carcinoma.

Undifferentiated/dedifferentiated endometrial carcinoma (UEC/DEC, collectively referred to as UDEC) is a rare but highly aggressive subtype of endometrial cancer, characterized by strong metastatic potential, frequent recurrence, and resistance to conventional chemotherapy. Currently, there is no standardized treatment strategy for UDEC. Genomic profiling has revealed a high frequency of PTEN mutations, resulting in dysregulation of the PI3K/AKT/mTOR and cell cycle pathways. To investigate therapeutic options, we utilized patient-derived xenograft (PDX) and tumoroid models established from PDX tumors derived from UDEC patient samples to evaluate everolimus (an mTOR inhibitor) and palbociclib (a CDK4/6 inhibitor), alone and in combination. Combination therapy exhibited antitumor effects in UDEC cell lines and tumoroids and significantly suppressed tumor growth in PDX models without inducing weight loss in mice. RNA sequencing of treated PDX tumors identified survivin as a consistently downregulated target. Mechanistically, the combination reduced Sp1-mediated transcription of survivin. In a clinical cohort of 29 UDEC patients, higher survivin expression showed a trend toward shorter overall and progression-free survival, supporting its role as a prognostic biomarker. These findings highlight dual PI3K/AKT/mTOR and CDK4/6 inhibition as a promising strategy for UDEC and demonstrate the translational value of PDX and tumoroid models in aggressive gynecologic cancers.